tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis
Authors: Kris V Kowdley, Christopher L Bowlus, Cynthia Levy, Ulus S Akarca, Mario Reis Alvares-da-Silva, Pietro Andreone, Marco Arrese, Christophe Corpechot, Sven M Francque, Michael A Heneghan, Pietro Invernizzi, David Jones, Frederik C Kruger, Eric Lawitz, Marlyn J Mayo, Mitchell L Shiffman, Mark G Swain, José Miguel Valera, Victor Vargas, John M Vierling, Alejandra Villamil, Carol Addy, Julie Dietrich, Jean-Michel Germain, Sarah Mazain, Dragutin Rafailovic, Bachirou Taddé, Benjamin Miller, Jianfen Shu, Claudia O Zein, Jörn M Schattenberg
Journal: New England Journal of Medicine (2023)

Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).
Breast Cancer Screening and Prevention
Authors: Amy H. Farkas, Ann B. Nattinger
Journal: Annals of Internal Medicine (2023)

Breast cancer is the most common cancer among U.S. women and its incidence increases with age. Endogenous estrogen exposure, proliferative benign breast disease, breast density, and family history may also indicate increased risk for breast cancer. Early detection with screening mammography reduces breast cancer mortality, but the net benefits vary by age. Assessing a patient's individual breast cancer risk can guide decisions regarding breast cancer screening. All women benefit from healthy behaviors which may reduce breast cancer risk. Some women at increased risk for breast cancer may benefit from risk-reducing medications. Use of screening measures remains suboptimal, especially for uninsured women.
SARS-CoV-2 Virologic Rebound With Nirmatrelvir–Ritonavir Therapy
Authors: Gregory E. Edelstein, Julie Boucau, Rockib Uddin, Caitlin Marino, May Y. Liew, Mamadou Barry, Manish C. Choudhary, Rebecca F. Gilbert, Zahra Reynolds, Yijia Li, Dessie Tien, Shruti Sagar, Tammy D. Vyas, Yumeko Kawano, Jeffrey A. Sparks, Sarah P. Hammond, Zachary Wallace, Jatin M. Vyas, Amy K. Barczak, Jacob E. Lemieux, Jonathan Z. Li, Mark J. Siedner
Journal: Annals of Internal Medicine (2023)

Background: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir−ritonavir (N-R) and virologic rebound (VR). Objective: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19. Design: Observational cohort study. Setting: Multicenter health care system in Boston, Massachusetts. Participants: Ambulatory adults with acute COVID-19 with and without use of N-R. Intervention: Receipt of 5 days of N-R treatment versus no COVID-19 therapy. Measurements: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL. Results: Compared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected. Limitations: Observational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission. Conclusion: Virologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus. Primary Funding Source: National Institutes of Health.
Development of miR-26a-activated scaffold to promote healing of critical-sized bone defects through angiogenic and osteogenic mechanisms
Authors: Joanna M. Sadowska, Monika Ziminska, Cole Ferreira, Austyn Matheson, Auden Balouch, Jasmine Bogle, Samantha Wojda, John Redmond, Ahmed Elkashif, Nicholas Dunne, Helen O. McCarthy, Seth Donahue, Fergal J. O'Brien
Journal: Biomaterials (2023)

Very large bone defects significantly diminish the vascular, blood, and nutrient supply to the injured site, reducing the bone's ability to self-regenerate and complicating treatment. Delivering nanomedicines from biomaterial scaffolds that induce host cells to produce bone-healing proteins is emerging as an appealing solution for treating these challenging defects. In this context, microRNA-26a mimics (miR-26a) are particularly interesting as they target the two most relevant processes in bone regeneration-angiogenesis and osteogenesis. However, the main limitation of microRNAs is their poor stability and issues with cytosolic delivery. Thus, utilising a collagen-nanohydroxyapatite (coll-nHA) scaffold in combination with cell-penetrating peptide (RALA) nanoparticles, we aimed to develop an effective system to deliver miR-26a nanoparticles to regenerate bone defects in vivo. The microRNA-26a complexed RALA nanoparticles, which showed the highest transfection efficiency, were incorporated into collagen-nanohydroxyapatite scaffolds and in vitro assessment demonstrated the miR-26a-activated scaffolds effectively transfected human mesenchymal stem cells (hMSCs) resulting in enhanced production of vascular endothelial growth factor, increased alkaline phosphatase activity, and greater mineralisation. After implantation in critical-sized rat calvarial defects, micro CT and histomorphological analysis revealed that the miR-26a-activated scaffolds improved bone repair in vivo, producing new bone of superior quality, which was highly mineralised and vascularised compared to a miR-free scaffold. This innovative combination of osteogenic collagen-nanohydroxyapatite scaffolds with multifunctional microRNA-26a complexed nanoparticles provides an effective carrier delivering nanoparticles locally with high efficacy and minimal off-target effects and demonstrates the potential of targeting osteogenic-angiogenic coupling using scaffold-based nanomedicine delivery as a new "off-the-shelf" product capable of healing complex bone injuries.
Paradoxical Response to Standardized Chest Loading May Unveil Occult Overdistension During Protective Ventilation
Authors: Elsa Moncomble, Samuel Tuffet, Mohamed Boujelben, Ségolène Gendreau, Pascale Labedade, Anne-Fleur Haudebourg, Armand Mekontso Dessap, Guillaume Carteaux
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Paradoxical Response to Standardized Chest Loading May Unveil Occult Overdistension During Protective Ventilation." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Sleep-Related Hypoxia, Right Ventricular Dysfunction, and Survival in Patients With Group 1 Pulmonary Arterial Hypertension
Authors: Megan M. Lowery, Nicholas S. Hill, Lu Wang, Erika B. Rosenzweig, Aparna Bhat, Serpil Erzurum, J. Emanuel Finet, Christine L. Jellis, Sunjeet Kaur, Deborah H. Kwon, Rawan Nawabit, Milena Radeva, Gerald J. Beck, Robert P. Frantz, Paul M. Hassoun, Anna R. Hemnes, Evelyn M. Horn, Jane A. Leopold, Franz P. Rischard, Reena Mehra, N. Hill, L. Xiao, Y.-P. Fu, L. Postow, B. Schmetter, K. Stanton, X. Tian, M. Gray, B. Wong, J. Leopold, A. Waxman, M. DiCarli, L. Lawler, B. Maron, S. Segrera, D. Systrom, P. Yu, E.B. Rosenzweig, S. Arcasoy, D. Brady, W. Chung, D. Payne, G. Grunig, J. Haythe, U. Krishnan, E. Horn, K. Akat, A. Borczuk, R. Devereux, J. Gordon, R. Kaner, M. Karas, J. Min, N. Narula, M. Ricketts, I. Sobol, R. Spiera, H. Singh, T. Tuschl, J. Weinsaft, P. Hassoun, S. Mathai, K. Barnes, R. Damico, B. Enobun, L. Gao, M. Halushka, D. Kass, T. Kolb, T. Lin, R. Tedford, S. Zimmerman, R. Frantz, A. Behfar, L. Block, B. Borlaug, L. Durst, T. Foley, T. Hammer, B. Johnson, G. Johnson, G. Kane, M. Krowka, A. McNallan, T. Olson, M. Redfield, K. Rohwer, A. Terzic, E. Williamson, F. Rischard, J. Yuan, A. Abidov, J. Garcia, A. Cordery, A. Desai, H. Erickson, L. Hansen, Z. Khalpey, K. Knox, Y. Lussier, M. Simon, R. Vanderpool, A. Hemnes, J. Newman, E. Austin, E. Brittain, J. Cunningham, C. LaRochelle, M. Pugh, I. Robbins, L. Wheeler, G. Beck, S. Erzurum, M. Aldred, K. Asosingh, J. Barnard, C. Collart, S. Comhair, F. DiFilippo, J. Drinko, R. Dweik, A. Flinn, M. Geraci, B. Hu, W. Jaber, M. Jacob, C. Jellis, S. Kalhan, K. Kassimatis, J. Kirsop, M. Koo, D. Kwon, B. Larive, J. Lempel, M. Li, J. MacKrell, B. Matuska, K. McCarthy, R. Mehra, D. Neumann, R. Nawabit, M. Olman, M. Park, M. Radeva, J. Sharp, S. Sherer, W. Tang, J. Thomas, K. Wiggins, B. Willard, S. Rounds, R. Benza, T. Bull, J. Cadigan, J. Fang, M. Gomberg-Maitland, G. Page
Journal: Journal of the American College of Cardiology (2023)
Challenges and Controversies in Peer Review
Authors: Fred M. Kusumoto, John A. Bittl, Mark A. Creager, Harold L. Dauerman, Anuradha Lala, Mary M. McDermott, Justine Varieur Turco, Viviany R. Taqueti, Valentin Fuster
Journal: Journal of the American College of Cardiology (2023)
Long-Term Outcomes of Invasive vs Conservative Strategies for Older Patients With Non–ST-Segment Elevation Acute Coronary Syndromes
Authors: Erlend S. Berg, Nicolai K. Tegn, Michael Abdelnoor, Kjetil Røysland, Pål Christie Ryalen, Lars Aaberge, Christian Eek, Erik Øie, Vibeke Juliebø, Erik Gjertsen, Anette Hylen Ranhoff, Lars Gullestad, Njord Nordstrand, Bjørn Bendz
Journal: Journal of the American College of Cardiology (2023)

Non–ST-segment elevation acute coronary syndrome (NSTE-ACS) is a frequent cause of hospital admission in older people, but clinical trials targeting this population are scarce. The After Eighty Study assessed the effect of an invasive vs a conservative treatment strategy in a very old population with NSTE-ACS. Between 2010 and 2014, the investigators randomized 457 patients with NSTE-ACS aged ≥80 years (mean age 85 years) to an invasive strategy involving early coronary angiography with immediate evaluation for revascularization and optimal medical therapy or to a conservative strategy (ie, optimal medical therapy). The primary endpoint was a composite of myocardial infarction, need for urgent revascularization, stroke, and death. The long-term outcomes are presented. After a median follow up of 5.3 years, the invasive strategy was superior to the conservative strategy in the reduction of the primary endpoint (incidence rate ratio: 0.76; 95% CI: 0.63-0.93; P = 0.0057). The invasive strategy demonstrated a significant gain in event-free survival of 276 days (95% CI: 151-400 days; P = 0.0001) at 5 years and 337 days (95% CI: 123-550 days; P = 0.0001) at 10 years. These results were consistent across subgroups of patients with respect to major cardiovascular prognostic factors. In patients aged ≥80 years with NSTE-ACS, the invasive strategy was superior to the conservative strategy in the reduction of composite events and demonstrated a significant gain in event-free survival. (The After Eighty Study: a randomized controlled trial; NCT01255540)
Exercise Stress Echocardiography of the Right Ventricle and Pulmonary Circulation
Authors: Luna Gargani, Nicola Riccardo Pugliese, Nicolò De Biase, Matteo Mazzola, Gergely Agoston, Michele Arcopinto, Paola Argiento, William F. Armstrong, Francesco Bandera, Filippo Cademartiri, Andreina Carbone, Rossana Castaldo, Rodolfo Citro, Rosangela Cocchia, Veronica Codullo, Michele D’Alto, Antonello D'Andrea, Philipp Douschan, Iacopo Fabiani, Francesco Ferrara, Monica Franzese, Paolo Frumento, Stefano Ghio, Ekkehard Grünig, Marco Guazzi, Jaroslaw D. Kasprzak, Theodore Kolias, Gabor Kovacs, André La Gerche, Giuseppe Limogelli, Alberto Maria Marra, Marco Matucci-Cerinic, Ciro Mauro, Antonella Moreo, Lorenza Pratali, Brigida Ranieri, Salvatore Rega, Lawrence Rudski, Rajan Saggar, Andrea Salzano, Walter Serra, Anna A. Stanziola, Mani A. Vannan, Damien Voilliot, Olga Vriz, Karina Wierzbowska-Drabik, Antonio Cittadini, Robert Naeije, Eduardo Bossone, Eduardo Bossone, Luna Gargani, Robert Naeije, Francesco Ferrara, William F. Armstrong, Theodore John Kolias, Valentina Capone, Rosangela Cocchia, Ciro Mauro, Chiara Sepe, Filippo Cademartiri, Iacopo Fabiani, Francesco Capuano, Rodolfo Citro, Rossella Benvenga, Michele Bellino, Giuseppe Iuliano, Serena Migliarino, Ilaria Radano, Antonio Cittadini, Michele Arcopinto, Alberto Marra, Giulia Crisci, Roberta D’Assante, Mariarosaria De Luca, Federica Giardino, Carmen Rainone, Salvatore Rega, Valeria Valente, Michele D’Alto, Paola Argiento, Antonello D’Andrea, Francesco Ferrara, Valentina Russo, Luna Gargani, Paolo Frumento, Matteo Mazzola, Santo Dellegrottaglie, Giovanni Di Salvo, Stefano Ghio, Stefania Guida, Ekkerard Grunig, Christina A. Eichstaedt, Marco Guazzi, Francesco Bandera, Valentina Labate, André La Gerch, Giuseppe Limongelli, Andreina Carbone, Giuseppe Pacileo, Marina Verrengia, Jaroslaw D. Kasprzak, Karina Wierzbowska-Drabik, Gabor Kovacs, Philipp Douschan, Antonella Moreo, Francesca Casadei, Benedetta De Chiara, Robert Naeije, Ellen Ostenfeld, Gianni Pedrizzetti, Marco Matucci-Cerinic, Francesco Pieri, Fabio Mori, Alberto Moggi-Pignone, Lorenza Pratali, Mauro Raciti, Nicola Pugliese, Nicolò De Biase, Gennaro D’Angelo, Brigida Ranieri, Rossana Castaldo, Monica Franzese, Andrea Salzano, Lawrence Rudski, Rajan Saggar, Walter Serra, Anna Agnese Stanziola, D’Angelo Rossella, Lorena Gallotta, István Szabó, Albert Varga, Gergely Agoston, Damien Voilliot, Olga Vriz, Domenico Galzerano, Mani Vannan, Sara Mobasseri, Peter Flueckiger, Shizhen Liu
Journal: Journal of the American College of Cardiology (2023)
Multifunctional Regeneration Silicon‐Loaded Chitosan Hydrogels for MRSA‐Infected Diabetic Wound Healing
Authors: Jingchen Xu, Yao Lin, Yue Wang, Hongyu Gao, Yuanhong Li, Chaoliang Zhang, Qianming Chen, Song Chen, Qiang Peng
Journal: Advanced Healthcare Materials (2023)

Abstract Repeated microbial infection, excess reactive oxygen species (ROS) accumulation, cell dysfunction, and impaired angiogenesis under hyperglycemia severely inhibit diabetic wound healing. Therefore, developing multifunctional wound dressings accommodating the complex microenvironment of diabetic wounds is of great significance. Here, a multifunctional hydrogel (Regesi‐CS) is prepared by loading regeneration silicon (Regesi) in the non‐crosslinked chitosan (CS) solution, followed by freeze‐drying and hydration. As expected, the blank non‐crosslinked CS hydrogel (1%) shows great antibacterial activity against Escherichia coli , Staphylococcus aureus , and methicillin‐resistant S. aureus (MRSA), improves fibroblast migration, and scavenges intracellular ROS. Interestingly, after loading 1% Regesi, the Regesi‐CS (1%‐1%) hydrogel shows greater antibacterial activity, significantly promotes fibroblasts proliferation and migration, scavenges much more ROS, and substantially protects fibroblasts under oxidative stress, yet Regesi alone has no or even negative effects. In the MRSA‐infected diabetic wound model, Regesi‐CS (1%‐1%) hydrogel effectively promotes wound healing by eliminating bacterial infection, enhancing granulation tissue formation, promoting collagen deposition, and improving angiogenesis. In conclusion, Regesi‐CS hydrogel may be a potential wound dressing for the effective treatment and management of chronic diabetic wounds.
Studying Long QT Syndrome Caused by <i>NAA10</i> Genetic Variants Using Patient-Derived Induced Pluripotent Stem Cells
Authors: Nadjet Belbachir, Yiyang Wu, Mengcheng Shen, Sophia L. Zhang, Joe Z. Zhang, Chun Liu, Bjorn C. Knollmann, Gholson J. Lyon, Ning Ma, Joseph C. Wu
Journal: Circulation (2023)
Engineered organoids for biomedical applications
Authors: Natan Roberto de Barros, Canran Wang, Surjendu Maity, Arne Peirsman, Rohollah Nasiri, Anna Herland, Menekse Ermis, Satoru Kawakita, Bruna Gregatti Carvalho, Negar Hosseinzadeh Kouchehbaghi, Rondinelli Donizetti Herculano, Zuzana Tirpáková, Seyed Mohammad Hossein Dabiri, Jean Lucas Tanaka, Natashya Falcone, Auveen Choroomi, RunRun Chen, Shuyi Huang, Elisheva Zisblatt, Yixuan Huang, Ahmad Rashad, Danial Khorsandi, Ankit Gangrade, Leon Voskanian, Yangzhi Zhu, Bingbing Li, Mohsen Akbari, Junmin Lee, Mehmet Remzi Dokmeci, Han-Jun Kim, Ali Khademhosseini
Journal: Advanced Drug Delivery Reviews (2023)
Targeting the apelin system for the treatment of cardiovascular diseases
Authors: Fiona A Chapman, Janet J Maguire, David E Newby, Anthony P Davenport, Neeraj Dhaun
Journal: Cardiovascular Research (2023)

Abstract Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism.
A Multicenter, Single-Blind, Randomized, Warfarin-Controlled Trial of Edoxaban in Patients With Chronic Thromboembolic Pulmonary Hypertension: KABUKI Trial
Authors: Kazuya Hosokawa, Hiroko Watanabe, Yu Taniguchi, Nobutaka Ikeda, Takumi Inami, Satoshi Yasuda, Toyoaki Murohara, Masaru Hatano, Yuichi Tamura, Jun Yamashita, Koichiro Tatsumi, Ichizo Tsujino, Yuko Kobayakawa, Shiro Adachi, Nobuhiro Yaoita, Shun Minatsuki, Koji Todaka, Keiichi Fukuda, Hiroyuki Tsutsui, Kohtaro Abe
Journal: Circulation (2023)
Microbial ligand-independent regulation of lymphopoiesis by NOD1
Authors: Chiaki Iwamura, Hidetaka Ohnuki, Francis A Flomerfelt, Lixin Zheng, Alexie Carletti, Hidefumi Wakashin, Yohei Mikami, Stephen R Brooks, Yuka Kanno, Ronald E Gress, Giovanna Tosato, Toshinori Nakayama, John J O'Shea, Alan Sher, Dragana Jankovic
Journal: Nature Immunology (2023)
Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma
Authors: Itske Fraterman, Irene L. M. Reijers, Petros Dimitriadis, Annegien Broeks, M. Gonzalez, A. M. M. Menzies, Marta Lopez-Yurda, Ellen Kapiteijn, Astrid A. M. van der Veldt, Karijn P. M. Suijkerbuijk, Geke A. P. Hospers, Georgina V. Long, Christian U. Blank, Lonneke V. van de Poll-Franse
Journal: Nature Medicine (2023)
IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial
Authors: Lindsay Ackerman, Gerard Acloque, Sandro Bacchelli, Howard Schwartz, Brian J. Feinstein, Phillip La Stella, Afsaneh Alavi, Ashwin Gollerkeri, Jeffrey Davis, Veronica Campbell, Alice McDonald, Sagar Agarwal, Rahul Karnik, Kelvin Shi, Aimee Mishkin, Jennifer Culbertson, Christine Klaus, Bradley Enerson, Virginia Massa, Eric Kuhn, Kirti Sharma, Erin Keaney, Randy Barnes, Dapeng Chen, Xiaozhang Zheng, Haojing Rong, Vijay Sabesan, Chris Ho, Nello Mainolfi, Anthony Slavin, Jared A. Gollob
Journal: Nature Medicine (2023)

Abstract Toll-like receptor–driven and interleukin-1 (IL-1) receptor–driven inflammation mediated by IL-1 receptor–associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600–1,600 mg and after 14 daily doses of ≥95% at 50–200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .